Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Central South University, Changsha, Hunan 410008, China.
Theranostics. 2022 Oct 31;12(17):7532-7549. doi: 10.7150/thno.77528. eCollection 2022.
The recurrence of cutaneous squamous cell carcinoma (cSCC) after surgery is associated with the reprogramming of the tumor microenvironment (TME), and remains a key factor affecting its outcomes. We employed single-cell RNA sequencing (scRNA-seq) to examine the dynamic changes in epithelial cells, T cells, myeloid cells, and fibroblasts between primary and recurrent cSCC. Cell clustering, cell trajectory, cell-cell communication, and gene set enrichment analysis were used to investigate the TME heterogeneity between primary and recurrent cSCC. Gene expression differences were monitored by IHC staining. We examined the immunosuppressed microenvironment in recurrent cSCC, which exhibited a T cell-excluded and SPP1 tumor-associated macrophages (TAMs)-enriched status. In recurrent cSCC, CD8 T cells showed high exhaustion and low inflammatory features, while SPP1 TAMs displayed global pro-tumor characteristics, including decreased phagocytosis and inflammation and increased angiogenesis. Furthermore, the subgroups of SPP1 TAMs harbored distinct functions. SPP1 CD209 TAMs showed features of phagocytosis, while SPP1 CD209 TAMs tended to have a high angiogenic ability. A subpopulation of tumor-specific keratinocytes (TSKs) showed significant epithelial-mesenchymal transition (EMT) features in recurrent cSCC, probably due to their active communication with IL7R cancer-associated fibroblasts (CAFs). Moreover, we found that the pleiotropic growth factor/cytokine Midkine (MDK) could provoke different cell-cell interactions in cSCC with distinctive staging. In primary cSCC, MDK was highly expressed in fibroblasts and could promote their proliferation and block the migration of tumor cells, while in recurrent cSCC, the high expression of MDK in TSKs promoted their proliferation and metastasis. Our study provides insights into the critical mechanisms of cSCC progression, which might facilitate the development of a powerful approach for the prevention and treatment of cSCC recurrence.
手术后皮肤鳞状细胞癌 (cSCC) 的复发与肿瘤微环境 (TME) 的重编程有关，仍然是影响其预后的关键因素。我们采用单细胞 RNA 测序 (scRNA-seq) 技术研究原发性和复发性 cSCC 上皮细胞、T 细胞、髓样细胞和成纤维细胞之间的动态变化。通过细胞聚类、细胞轨迹、细胞间通讯和基因集富集分析，研究原发性和复发性 cSCC 之间 TME 的异质性。通过免疫组织化学染色监测基因表达差异。我们研究了复发性 cSCC 中免疫抑制的微环境，该环境表现出 T 细胞排斥和 SPP1 肿瘤相关巨噬细胞 (TAMs) 富集的状态。在复发性 cSCC 中，CD8 T 细胞表现出高衰竭和低炎症特征，而 SPP1 TAMs 则表现出整体促肿瘤特征，包括吞噬作用和炎症减少以及血管生成增加。此外，SPP1 TAMs 的亚群具有不同的功能。SPP1 CD209 TAMs 表现出吞噬作用的特征，而 SPP1 CD209 TAMs 往往具有较高的血管生成能力。复发性 cSCC 中肿瘤特异性角蛋白细胞 (TSKs) 的一个亚群表现出明显的上皮间质转化 (EMT) 特征，这可能是由于它们与 IL7R 癌症相关成纤维细胞 (CAFs) 的活跃通讯所致。此外，我们发现多效生长因子/细胞因子 Midkine (MDK) 在具有不同分期的 cSCC 中可以引发不同的细胞间相互作用。在原发性 cSCC 中，MDK 在成纤维细胞中高表达，并能促进其增殖并阻止肿瘤细胞的迁移，而在复发性 cSCC 中，MDK 在 TSKs 中的高表达促进了其增殖和转移。我们的研究为 cSCC 进展的关键机制提供了深入了解，这可能有助于开发预防和治疗 cSCC 复发的有效方法。
